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Genetische neurologische aandoeningen

Dr. Rhiannon Meredith

Universitair Docent Integratieve Neurofysiologie

Vrije Universiteit Amsterdam

1. Wat is de belangrijkste wetenschappelijke ontwikkeling in uw vakgebied?

We are investigating the basis of genetic neurodevelopmental disorders including intellectual disability and autism. These disorders alter the function of neurons in the brain and impair learning behaviours. Excitingly, scientists have shown in recent experiments that some of these impaired neurons can be significantly improved or even ‘cured’ after drug treatment or genetic manipulation. These experiments are carried out using genetically engineered mice in the lab that have the same genetic disorder as humans with some types of intellectual disability and autism.

To give an example, scientists have used genetically engineered mice that have the same genetic deficit seen in people with an intellectual disability called Fragile X syndrome. Like humans, these mice have specific learning problems, are more prone to epileptic seizures and the synapses on neurons in their brains appear immature – just like in humans with Fragile X. A research group in the USA found that nerve cells in the brain of these Fragile X mice show enhanced responses through a specific protein in their membranes, called mGluR5. To find out whether this protein on nerve cells could be responsible for some of the symptoms in this syndrome, they bred Fragile X mice with another mouse strain that had less mGluR5 protein on nerve cells in the brain. To their amazement, the crossbred Fragile X mice with less mGluR5 protein showed improvements in 6 out of 7 measures of nerve cell activity and behaviour. These new mice were no different to normal mice in the lab. Similar effects have been seen more recently in experiments using drugs to decrease the mGluR5 activity in Fragile X mice nerve cells. These data were so exciting for the field that they have led to clinical trials. Young adults with Fragile X syndrome are now taking part in clinical trials to see if drugs that reduce the activity of the mGluR5 protein can help improve some of their symptoms associated with their condition.

It doesn’t mean that we can ‘cure’ or alleviate symptoms of these neurodevelopmental disorders in humans yet. However, the knowledge these experiments provide to scientists and doctors are a step in that direction.

2. Op welke wetenschappelijke doorbraak hoopt u?

A tool that would help us significantly in our work is to be able to identify different types of neurons in the brain and categorise them whilst they are still alive. We can identify some cells in the brain from their shape and their levels of functional activity. We can already visualise certain groups of cells in the brain, thanks to the technical development of engineering specific brain cells to express fluorescent proteins that glow in ultraviolet light – a technique which incidentally led to the Nobel Prize in Chemistry in 2008. However, using this technique we still can’t, for example, easily distinguish all the many different inputs that make connections with a neuron in the frontal cortex part of the brain. One neuron can receive a different pattern of connections to its neighbour but we can’t yet visualise them all in living tissue. Knowledge of what tags or genetic markers can identify these different neuron connections would be a great help to our research. We could look at whether the genetic problems in neurodevelopmental disorders affect specific types of neurons and connections in the brain more than other types. And since these fluorescent proteins can be expressed while the brain is growing, we can see whether changes in the way the brain and its neurons develop are occurring much earlier than we think in these disorders, before any behavioural impairments can be seen.

3. Wat is de waarde van uw vakgebied voor de samenleving?

Our research focuses on the early development of neurons in the brain, particularly in mice that are genetic models for neurodevelopmental brain disorders. Our experiments give us an insight into how the genetic deficit in these disorders alters neuron activity in the brain. To do this, we carry out our experiments using brain tissue from mice that have the same genetic mutation as humans with these disorders, such as Fragile X syndrome. We can also test drugs, particularly in young mice to see whether they can correct the symptoms caused by the genetic deficit. Our results don’t directly lead to a therapy or drug treatment in the clinic. However, the knowledge we gain from studying the early neuron deficits in these disorders tells us that there may be impairments in the brain long before symptoms can be seen in these neurodevelopmental disorders. Identifying when these changes occur and how the genes cause these impairments will be invaluable in the development of future therapies.